Lec 7: Inflammation

Question 1

What is the main function of inflammation?

Answer 1

• remove infection or damaged tissue to restore homeostasis
• crucial to maintaining the health and integrity of an organism
• soluble mediators and cellular components work together in a systemic fashion

Question 2

What 2 responses is inflammation divided into?

Answer 2

acute and chronic

Question 3

What are the 4 physiological changes that accompany acute inflammation?

Answer 3

• vasodilation
• permeability
• recruitment of leukocytes
• fever

Question 4

What are the 4 clinical signs that accompany acute inflammation?

Answer 4

• rubor (redness)
• dolor (pain)
• calor (heat)
• tumor (swelling)

Question 5

Describe vasodilation

Answer 5

• one of the earliest physical responses to acute tissue injury
• arterioles are the first to be involved, followed by the capillary beds, resulting in a net increase in blood flow
• increased blood flow results in the characteristic heat and redness associated with foci of acute inflammation

Question 6

Describe vascular permeability

Answer 6

• under normal conditions, vascular endothelial cells function as a semi-permeable membrane, restricting the plasma proteins to the intravascular space
• in response to inflammatory stimuli, endothelial cells lining the venues contract, widening the intercellular junctions to produce gaps, permitting passage of plasma proteins and facilitating leukocyte extravasation.
• more severe injury is associated with endothelial cell necrosis

Question 7

Describe leukocyte recruitment

Answer 7

• process recruits leukocytes from bloodstream and ultimately involves the bone marrow to focus on inflammatory activity
• these leukocytes migrate through the enlarged endothelial cell junctions and the basement membrane

Question 8

Describe fever.

Answer 8

• agents producing fever (pyrogens) are released from leukocytes in response to specific stimuli, such as bacterial endotoxin
• a number of soluble pro inflammatory mediators have been implicated in this process (IL1, TNFa) and prostaglandins
• possible beneficial role of fever with respect to lymphocyte trafficking

Question 9

Describe what can be seen with inflammation at the microscopic scale?

Answer 9

• dilated post capillary venules
• leukocytes marginating on epithelia
• mild expansion of superficial dermis
• edema

Question 10

How is inflammation initiated?

Answer 10

• innate immune recognition triggers an inflammatory response that focuses the immune system on the site of infection
• inflammation requires the coordinated response from blood vessels and leukocytes

Question 11

Describe the 3 things that can trigger inflammation.

Answer 11

1. pathogens: activation of the plasma protease systems by interaction with degradation products of the bacterial cell walls; secretion of toxins
2. injured cells: release degradation products that initiate one or more of the plasma protease cascades; up regulate expression of soluble molecules (pro inflammatory cytokines)
3. foreign bodies from exogenous or endogenous sources, physical injury, chemical agents

Question 12

Describe how TLRs initiate pro inflammatory responses.

Answer 12

• first line of defence against incoming pathogens
• well conserved across evolution
• remember that they work together with several other types of recognition receptors (e.g. resident macrophages, epithelial cells)

Question 13

Describe the TLR signalling pathway.

Answer 13

TLRS - MyD88 dependent or indepndent pathways - transcription factors - gene expression - functional protein - cellular response

Question 14

Why do TLRs share many cellular responses?

Answer 14

• share MyD88 and NfKb

Question 15

What are the 3 types of inflammatory mediators?

Answer 15

• cytokines
• chemokines
• hormones

Question 16

Describe cytokines

Answer 16

• polypeptide signaling molecules that participates in immune responses
• often act locally (in an autocrine or paracrine manner) but can act systemically
• most are secreted molecules but membrane bound versions often occur

Question 17

Describe chemokines.

Answer 17

• family of closely related small basic cytokines
• main function is as chemoattractants
• name is a contraction of a chemotactic cytokine

Question 18

Describe hormones

Answer 18

• biomolecules synthesized in small amounts by ductless (endocrine) glands: polypeptide, amide, or steroid
• travel from site of synthesis to distant target tissues
• mediate regulatory effects by binding to specific cell surface receptors - intracellular receptors in case of steroid hormones

Question 19

What are the 4 main actions of inflammatory regulators?

Answer 19

• induce vascular permeability to allow the influx of soluble immune components from the blood
• change the adhesive properties of the endothelium to attract more phagocytes to the site of infection
• activate the incoming leukocytes to promote their microbicidal action
• induce production of complementary cytokines: early positive feedback to amplify pro inflammatory response; later negative feedback to induce anti inflammatory response

Question 20

Describe TNF

Answer 20

• derived primarily from activated macrophages
• associated with the production of fever, and similar to IL1, promotes the increased expression of most other pro inflammatory mediators, and it is prominently associated with the induction of cellular apoptosis

Question 21

Describe IL-1

Answer 21

• major inflammatory mediator
• produced primarily by monocytes and activated macrophages
• high affinity receptors for IL1 are found on lymphocytes and fibroblasts
• numerous local and systemic pro inflammatory activities: increasing local blood flow, fever, production of other soluble mediators, and enhanced expression of adhesion molecules

Question 22

Describe IL-6

Answer 22

• produced by T lymphocytes, endothelial cells, monocytes, and fibroblasts
• wide reaching effects on T and B lymphocytes and macrophages, including promoting monocyte differentiation, increased number of circulating platelets, and synthesis of acute phase reactant proteins (including fibrinogen) in the liver
  = kinetics of production: after IL1 and TNF
• involved in neutrophil to monocyte shift in recruitment

Question 23

Describe IL12

Answer 23

• heterodimeric product of macrophages and B lymphocytes
• enhances the synthesis of IFN-y and stimulates proliferation of NK, Th1 cells, and cytotoxic T lymphocytes
• role in host defines against intracellular bacteria

Question 24

Describe the importance of cytokines regulating TH1 and TH2 responses.

Answer 24

• shift balance to ‘hone in’ on the best response
• relevance to normal physiological changes (e.g. TH2 pregnancy and susceptibility)
• pathogens can also take advantage of this to evade host defenses (e.g. parasites)

Question 25

What are the 4 main cell types involved in acute inflammation?

Answer 25

1. macrophages: resident tissue macrophages key in both initiation and resolution; orchestrate responses 2. neutrophils: recruited first; possess a large array of inflammatory mediators 3. monocytes: inflammatory monocytes recruited by neutrophils an soluble mediators; divide and differentiate into macrophages and DCs 4. lymphocytes: adaptive mechanisms to control infection

Question 26

Describe leukocyte extravasation.

Answer 26

- important for kinetics of inflammatory response - early during a bacterial infection neutrophil chemokines are expressed - chemokine signalling activates interns which mediate firm adhesion to the endothelium - diapedesis follows: the process of moving through 2 endothelial cells - chemotaxis within the tissue to locate the site of infection and immune attack on pathogen

Question 27

Describe why the leukocyte shift occurs.

Answer 27

- inflammation triggered by bacterial infection is initially dominated by neutrophils - neutrophils - monocytes - lymphocytes - why? Neutrophils are very destructive. Monocytes participate in immune defences but also wound healing (less destructive)

Question 28

Describe how chronic inflammation occurs.

Answer 28

- of longer duration than acute and includes influx of lymphocytes and macrophages - occurs when incomplete clearance of causative agent or due to multiple acute events at the same location - growth of fibroblasts and vascular tissue associated with scarring - tissue granulomas: collection of inflammatory cells surrounded by a fibrotic wall. Typical of intracellular bacterial infections as tuberculosis

Question 29

How is pro inflammatory cytokine activity regulated?

Answer 29

- occurs through a series of feedback inhibitory mechanisms - TNF induces shedding of TNF receptors - TNF induces production of tristetraprolin (inhibitor of TNF) - delayed production of macrophages of soluble IL-1R - macrophages produce IL10 and TGF-b

Question 30

How is inflammation regulated through cell to cell interactions?

Answer 30

- necrotic cell death promotes effect induction of inflammation